High Throughput Screening of Serum γ-Glutamyl Dipeptides for Risk Assessment of Nonalcoholic Steatohepatitis with Impaired Glutathione Salvage Pathway
| Autor: | Kazunori Sasaki, Tomomi Kogiso, Kaori Abe, Katsutoshi Tokushige, Hitoshi Sagawa, Michelle Saoi, Philip Britz-McKibbin, Yoshiaki Ohashi, Etsuko Hashimoto |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
0301 basic medicine medicine.medical_specialty Type 2 diabetes Risk Assessment digestive system Biochemistry Gastroenterology Liver disorder 03 medical and health sciences Non-alcoholic Fatty Liver Disease Tandem Mass Spectrometry Internal medicine Nonalcoholic fatty liver disease medicine Humans 030102 biochemistry & molecular biology business.industry Dipeptides General Chemistry Middle Aged medicine.disease Glutathione Obesity digestive system diseases Pathophysiology High-Throughput Screening Assays 3. Good health 030104 developmental biology Diabetes Mellitus Type 2 Liver Cohort Histopathology Risk assessment business |
| Zdroj: | Journal of Proteome Research. 19:2689-2699 |
| ISSN: | 1535-3907 1535-3893 |
| Popis: | Nonalcoholic fatty liver disease (NAFLD) is the most common preventable chronic liver disorder in developed countries, the prevalence of which is increasing worldwide due to its association with obesity and type 2 diabetes. However, the exact mechanisms of NAFLD pathophysiology remain poorly understood including its progression to the more severe nonalcoholic steatohepatitis (NASH). New advances for early detection and monitoring of NASH progression are limited due to the lack of specific blood biomarkers, thus requiring invasive liver biopsies for histopathology. Herein, multisegment injection-capillary electrophoresis-tandem mass spectrometry (MSI-CE-MS/MS) is validated as a high throughput, robust, and quantitative platform for targeted analysis of a panel of 16 serum γ-glutamyl dipeptides from a cohort of NASH adult patients from Japan (median age = 53 years, median BMI = 27 kg/m2, n = 116). Multiplexed separations based on MSI-CE-MS/MS enable the design of unique data workflows that rely on customizable serial sample injection formats for accurate determination of γ-glutamyl dipeptides with quality control. Also, the introduction of a liquid coolant device to the capillary outlet improves long-term migration time stability in CE. Unsupervised pattern recognition methods revealed two distinctive NASH subgroups based on their contrasting γ-glutamyl dipeptide status despite patients having similar clinical phenotypes and NASH activity scores (median NAS ≈ 6.0). There was an inverse correlation between serum γ-glutamyl dipeptide concentrations and γ-glutamyltransferease (GGT) enzyme activity (r = -0.46; p = 2.5 × 10-7), which was indicative of a low-risk (n = 64) as compared to a high-risk (n = 52) patient subgroup with impaired glutathione salvage pathway and likely poor clinical prognosis. Our findings highlight the key role of defects in the γ-glutamyl cycle for differentiation of NASH patients, which may enable better risk assessment of long-term survivorship as a complement to standard liver enzyme screens and histopathology. |
| Databáze: | OpenAIRE |
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